Migraine in the general population can greatly reduce quality of life. More than half of those with migraine report headaches lead to impaixBient in their daily lives. People with migraine suffer comprotnised physical, mental, and social functioning, as well as more chronic medical illnesses, such as asthma and musculoskeletal pain.1
The disability associated with migraine is often grossly underestimated. The total disability, which combines losses from premature death and loss of healthy life, attributable to migraine is equal to or exceeds that of several other major diseases, including hypertension, breast cancer, and rheumatoid arthritis.2
This article will discuss the relationship between migraine and mood disorders, primarily migraine and bipolar disorder, including prevalence rates as reported in the literature as well as treatment options. Headache definitions and the association between migraine and major depression are also reviewed.
The International Headache Society (IHS) has recently introduced an updated edition of their headache classification system, first published in 1988 (Sidebar I) to provide specific operational criteria for the major headache syndromes and to facilitate international standardization of the diagnostic nomenclature for headache syndromes.3 The new IHS criteria for migraine with or without aura are shown in Sidebars 2 and 3 (see pages 35 and 36). The criteria for migraine without aura are very similar to the 1988 version; however, the migraine with aura criteria now specify the nature of the reversible neurological dysfunction as having to be a visual, sensory, or speech disturbance and excludes motor weakness.3 The core features of most definitions of migraine include a recurrent, unilateral, throbbing or pulsating headache, exacerbated by physical activity and concomitant with gastrointestinal symptoms and hyperesthesia manifested by photophobia or phonophobia. The IHS criteria operationalize these features of headache to draw common thresholds and distinctions between migraine and other types of headache syndromes.
The second edition of the IHS classification system includes a category for "headache attributed to psychiatric disorder." The IHS recommends that this diagnosis be applied to cases of headache that resolve or greatly improve only after effective treatment or spontaneous remission of a psychiatric disorder. This category is controversial because of the lack of objective evidence regarding what constitutes a true somatic manifestation of a psychiatric disorder.
Comorbidity, a term introduced by Feinstem in 1 970, is defined as the presence of any additional coexisting ailmeat in a patient with a particular index disease.4 Lack of attention to diagnosis and classification of comorbid illness can lead to inaccurate medical reporting and spurious associations that may result in different evaluation and treatment for patients. Comorbidity can affect the clinical course of patients with the same diagnosis, including the time of detection, prognostic anticipations, therapeutic selection, and post-therapeutic outcome of an index diagnosis.5 It can also affect the length of hospitalization, response to medical treatment, and mortality.6-9
Since migraine was first described as a discrete syndrome, associations between it and a variety of medical and psychiatric conditions have been described in the literature)?'2 Because most of the early reports of such associations were based on clinical case series, empirical evidence was lacking. Several factors complicate the investigation of comorbidity of migraine and other conditions, such as the lack of identification of migraine equivalents, which are alternate expressions of migraine including attack-like occurrences of abdominal pain, dizziness or vertigo, or visual symptoms that may occur in isolation witbout headache. The instability of symptom expression or constellations within the same individual over time, and the involvement of multiple systems (ie, central and peripheral nervous system, gastrointestinal, cardiovascular), are also complicating factors.
There have been numerous writings on the comorbidity of migraine and psychiatric syndromes ranging from mood disorders to anxiety, including panic disorder, phobias, obsessive-compulsive disorder, and generalized anxiety disorder. 13-20 There are also data relating to migraine and somatoform (conversion and hypochondriasis),5 impulse control (ie, intermittent explosive disorder), eating, and substance-use disorders.1,21,23 Other aspects of mood disorders, such as dysthmia and suicidal ideation and attempts, have been reported, but are not addressed here.19,24,25
Migraine and Depression
Most of literature on the association between migraine and mood disorders has focussed on migraine and major depression. In studies examining the prevalence of depression in migraine patients from clinical settings (N = 40 to 500), the rates reported show a wide variation, from 3.8% to 57%,19,26-30 compared with general population lifetime rates ranging from 9% to 13%.31,32 Studies looking at the reverse relationship, the prevalence of migraine in depressed clinical populations with samples sizes between 116 and 423, found that migraine rates vary between 19% and 84%.33"36 The lower value of this range is comparable to general female rates of migraine (16%) but is much higher than that of males (6%).32
Of the community-based studies, with sample sizes of 15 to 17,626, all have demonstrated a positive association between depression and migraine, with odds ratios between 2 and 4, despite variation in the subject characteristics, geographic sites, and specific assessments of migraine and depression.14,15,17,37-40 Two additional community-based populations studied migraine prevalence among depressed men and women. Crisp et al.41 examined 772 subjects (379 females, 343 males) and found a migraine rate of 26% in women (P = not significant) and 10% in males (P < .004). Paulin et al.42 looked at 1,139 people with depression (590 females, 549 males) and found a migraine rate of 19% among females and 6% among males.
Taken together, these clinical and community studies provide substantial evidence for a positive association between migraine and major depression.
Migraine and Bipolar Disorder
To date, the evidence to support an association between bipolar disorder and migraine has not been as vigorously pursued. Six clinical populations of bipolar subjects have been examined for migraine.43"49 The largest study extracted a subsample of bipolar patients (N = 327, 186 females, 141 males) from the National Institute of Mental Health's Genetics Initiative to compare gender differences .43Migraine diagnosis was based on the medical history section of the Diagnostic Interview for Genetic Studies, which asks for a lifetime history of migraine. Female bipolar subjects reported a lifetime migraine history of 26.5%, compared with 13.7% for males (P < .005).
The next-largest study employed a clinician-adrninistered migraine - based on 1988 DHS criteria - and clinical questionnaire to assess 108 outpatient bipolar subjects.44 The migraine rate was reported as 39.8% overall, 43.8% among females, and 31.4% among males. The rate was 64.7% in the subgroup containing bipolar type II subjects. The subjects with bipolar and migraine were found to be younger, more educated and employed, and hospitalized fewer times compared with their counterparts without migraine.
Cassidy and Flanagan44 interviewed 100 patients hospitalized with bipolar disorder and compared them with 50 medically sick, age- and gender-matched controls in the same hospital. They administered a 188-item questionnaire that inquired about the subject's medical and neuropsychiatrie history. Using the selfreported prevalence of "headache," not specifically of migraine, they found significantly different rates of 49% among the bipolar group, compared with 36% among the medically sick control group.
Mahmood et al.45 looked at migraine prevalence in a sample of 81 bipolar subjects (37 females, 44 males) in New Zealand. The study reported migraine rates of 25% in the men and 27% in the women, using a voluntary mail-in questionnaire incorporating the IHS criteria to diagnose migraine. In the subjects who suffered from migraine, they found an earlier age of onset (younger than 25 years) of bipolar disorder, compared with the subjects without migraine (57% versus 36%, respectively).
Fas mer46,49 investigated 102 patients with mood disorder (52 with unipolar depression, 22 with bipolar type I, and 28 with bipolar type II) from in- and outpatient psychiatric sources. Migraine diagnosis was made using IHS criteria, and prevalence rates were reported by mood-disorder diagnosis. The migraine rate was 11% for subjects with bipolar type I and 43% for subjects with bipolar type II. The migraine- versus nonmigraine group comparisons of clinical characteristics were made in the overall study sample without stratification by subtype of affective disorder.
The smallest clinical sample studied was by Younes et al.,47 who employed a case-control design to investigate 21 male children with bipolar disorder who responded to lithium. They were matched with normal males whose mean age was 11. Migraine diagnosis was based on a questionnaire administered by telephone to the mothers of the children, and asked for a yes or no response concerning diagnosis of migraine headaches. The study reported that 28.6% of the group with bipolar disorder had a migraine history compared with 0% of the control group (P < .016).
These clinical populations reflect consistently elevated migraine rates above the general population, and the disparity is more pronounced when the migraine prevalence is divided on the basis of gender. The female bipolar population has a slightly higher prevalence than the general female population, but the male bipolar population has migraine rates of at least 2 to 5 times higher than the general male population.
Two studies have also investigated the relation between bipolar disorder and migraine among samples of people with migraine.17,50 In the United States, Robbins and Ludmer50 interviewed ,000 consecutive migraine patients for the presence of a lifetime history of bipolar disorder and cyclothymia, as defined by the Diagnostic and Statistical Manual for Mental Disorders, fourth edition, and additional bipolar spectrum diagnoses as developed by Akiskal.51 They found rates of 2. 1 % for subjects with bipolar type I, 2.4% for subjects with bipolar type II, 1.3% for subjects with cyclothymia, and 2.8% for subjects with bipolar not otherwise specified. Therefore, a total of 8.6% of the migraine sample had a bipolar spectrum disorder. This rate was similar to the rate of 8.8% found in Merikangas and Angst's study17 of a community population in Zurich, Switzerland. They evaluated the association between migraine and bipolar spectrum disorder, as defined by a manic or hypomanic episode. The rates found in both of these migraine populations are much higher than the usual 1% general population rate of bipolar disorder.
TREATMENT OF MIGRAINE
The US Headache Consortium52 has identified the following goals for long-term migraine treatment:
* reduce attack frequency and severity;
* reduce disability;
* improve quality of life;
* prevent headache;
* avoid headache medication escalation; and
* educate and enable patients to manage their disease.
Migraine treatment involves both nonpharmacologic and pharmacologic interventions. Non-pharmacologic treatment focuses on teaching patients to avoid triggers, including environmental stimuli such as noise, bright light, extreme temperatures, and smoke; specific foods such as caffeine, wine, chocolate, monosodium glutamate, nitrates in processed meats, aspartame, and citrus; and drugs such estrogens, nitroglycerine, and nicotine. Other patient strategies may also involve maximizing the regularity of daily schedule, particularly with respect to sleeping and eating habits, as well as biofeedback, regular exercise, and relaxation treatment.
Triptan Dosages for Acute Treatment of Migraine
Pharmacologic invention is the mainstay of migraine treatment and can be prophylactic, through daily medication, or abortive, with medication taken at the onset of the attack. Treatment can also be palliative, with medication taken after the pain has begun.
Prophylactic treatments for migraine are of varying effectiveness. Clinical trials of migraine treatments are complicated by the high placebo-response rate among subjects with migraine, the heterogeneity of diagnostic subtypes of headache, the intermittent nature of the condition, and the frequent use of additional analgesics to treat headache pain. The treatment of migraine selected for an individual depends not only on the diagnosis of migraine headache, but also on related factors specific to the patient.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including Ibuprofen, naproxen, indomethacin, and aspirin, and the analgesic acetominophen are commonly used as the first-line treatment for mild to moderate migraine. The over-the-counter formulation of acetominophen-aspirin-caffeine and is approved by the Food and Drug Administration for treatment of migraine, as are some Ibuprofen drugs.
Other classes of drugs commonly prescribed for more severe attacks include ergot derivatives, serotonin agonists, and narcotics. Eigotamine tartrate and dihydroergotamine are two of the most commonly prescribed ergot derivatives for moderate to severe attacks of migraine. They relieve pain by constricting cerebral and peripheral vessels through adrenergic blockade and also have serotonergic activity. Their major disadvantage is that they can cause nausea, vomiting, and coronary or peripheral ischemia. Metoclopramide or prochlorperazine are often used for the side effect of nausea.
Prophylactic Treatment of Migraine
Combination agents, generally comprising barbiturates, analgesics, and caffeine, are also highly effective in the treatment of migraine episodes. In general, narcotics should be restricted to severe attacks that are not responsive to other agents. Oral narcotic agents such as oxycodone do not cause addiction when used infrequently for acute attacks. However, chronic narcotic treatment is not appropriate for headache. Clinicians should be particularly cautious when prescribing drugs such as ergotamine and narcotics due to the risk of abuse and dependence, especially among patients with pre-existing addictions.
The triptans are 5-HT1D agonists that act by constricting cranial vessels and inhibiting release of pro-inflammatory neuropeptides. They have been used for the acute treatment of migraine since sumatriptan was first introduced in 1991. Although they were originally selfadministered subcutaneously, other modes of administration including oral preparations, nasal spray, and patch are now available for some of the triptans.
The triptans in current use include sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan, eletriptan, and frovatriptan (Table 1, see page 37). In general, the triptan compounds are much less likely to cause nausea and vomiting and are quite safe, but because of coronary vasoconstriction, they should be avoided in individuals with vascular disease. Factors to consider when choosing a triptan for an acute migraine attack include its time to onset, duration, likelihood of headache recurrence, and sideeffect profile. Recent research has shown that frovatriptan, for example, is effective in prolonged attacks as well as in migraine with a high probability of recurrence and migraine related to the menstrual cycle. Co-administration of serotonergic drugs with triptan compounds is particularly dangerous because of the risk of serotonin syndrome.
Prophylactic treatment of migraine should be considered in patients who experience frequent, debilitating attacks more than once a month, particularly if attacks occur more than twice a week. Patients who miss a substantial amount of work or school due to headache (ie, more than 3 days per month) are also candidates for migraine prophylaxis, as are those with comorbid disorders such as depression, anxiety, or epilepsy. Those who have not had success with acute treatments and those with less common afflictions, including hémiplégie migraine, basilar migraine, migraine with prolonged aura, or migrainous infarction, are also candidates.
The major classes of drugs that have been investigated in the prophylaxis of migraine headaches are beta-adrenergicblockers, antidepressants, calcium-channel blockers, and anticonvulsants. Table 2 presents these different classes and a range of recommended daily doses. Betablockers are the most popular treatment choice in migraine prophylaxis, yet the effect of this class of drugs is moderate at best. No study has reported complete elimination of migraine; however, average duration and severity are reduced by 50% in most subjects. Clinicians should be particularly cautious in prescribing this class of drugs to individuals with a history of depression because beta-blockers are associated with the development of anhedonia, irritability, and lassitude, which may occur even after many months on these agents. Patients with high levels of autonomic anxiety, however, may actually benefit from this class of drugs.
During the past few years, antiepileptics agents have been used to prevent migraine. Valproic acid and its derivatives are first-line treatment for bipolar disorder and have now been approved for migraine treatment. Therefore, they may be particularly useful in the presence of comorbid bipolar disorder. Other antiepileptic drugs that have been assessed for their efficacy in migraine include gabapentin, which has the advantage of very few drug-drug interactions, and topiramate, which has weight loss as a side effect.
Antidepressants, particularly the trieyclics, have been shown to be superior to the first-line agents of migraine treatment regardless of comorbid depression or anxiety, although patients continue to report the typical anticholinergic side effects. Tt is preferable to use the secondary amines (eg, nortriptyline and desimpramine) over parent tertiary amines (eg, amitriptyline and Imipramine), due to fewer side effects. However, the relative efficacy of the various tricyclic antidepressants in migraine prevention has not been examined.
Monoamine oxidase inhibitors (MAOIs), especially phenelzine, have been reported to be efficacious in the treatment of migraine headache, particularly in patients who have been unresponsive to the first-line prophylactic treatment.53'55 Clinicians, however, have generally been reluctant to prescribe MAOIs because of the possibility of hypertensive crises due to excessive dietary tyramine. The use of calciumchannel blockers to treat the hypertensive crisis associated with MAOIs may reduce clinicians' reservations about prescribing these agents.
Combinations of the above classes of drugs - for example, tricyclics combined with either beta-blockers or MAOIs - have also been applied in those cases that do not respond to firstline agents.
It should be noted that selective serotonin reuptake inhibitors (SSRIs) do not have demonstrated efficacy in migraine, and, in fact, many patients complain of headache as a secondary effect from them. Caution must be exercised when treating patients with depression who take SSRIs and who have comorbid migraine. These patients may also intermittently use triptans for acute symptomatic relief of a migraine attack, a scenario that increases the risk for serotonin syndrome.
Angiotensin-Converting enzyme (ACE) inhibitors, such as Captopril or enalapril, have been studied and have been found to be effective in the prevention of migraine.3 Several drugs used for the acute treatment of headache, such as aspirin and NSAIDs, may also be effective when used on a regular basis.
In summary, the goal of complete prevention of migraine on a long-term basis has not yet been achieved. Most of the migraine prophylaxis trials have shown that no agent has succeeded in reducing migraine attacks or severity by more than 50%. Scientists believe the disappointing results in migraine prevention are due to a lack of animal models and poor understanding of etiology of specific headache subtypes. Nevertheless, numerous drugs and combinations of drugs reduce the frequency and duration of migraine at the level of the individual case. Therefore, careful clinical management on a regular basis remains the best strategy to reduce the burden of headache.
Migraine and mood disorders are highly comorbid and each exerts a significant, independent, negative influence on health-related quality of life.54 Patients who suffer from psychiatric illnesses, especially major, depression, bipolar disorder, and schizophrenia, are also at great risk for an undetected medical illness.56 Psychiatrists are even more likely to miss medical diagnoses if the patient is older than age 35 and a woman,56 which is the age group and gender most often affected by migraine. Therefore, a number of factors establish psychiatric patients as having an especially high probability for underrecognized and undertreated migraine. These factors, in turn, may affect treatment choices, course, and prognosis of both migraine and the mood disorder.
Systematic evaluation of the lifetime history of all headache syndromes, especially migraine, is necessary for determining optimal treatment strategies. If there is a subtype of mood disorders associated with migraine, it is critical to treat the entire syndrome rather than limiting the treatment goal to the mood abnormality. Consideration of comorbid migraine in patients with mood disorders is important in the selection of migraine prophylaxis medications that have the possible side effects of lassitude, fatigue, or depression. Thoughtful prescribing practices in the treatment of both disorders may lead to improved compliance and decreased side-effect burden.
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Triptan Dosages for Acute Treatment of Migraine
Prophylactic Treatment of Migraine